Altered Toll-like Receptor 2-mediated Endotoxin Tolerance Is Related to Diminished Interferon β Production

Abstract

Induction of endotoxin tolerance leads to a reduced inflammatory response after repeated challenge by LPS and is important for resolution of inflammation and prevention of tissue damage. Enterobacterial LPS is recognized by the TLR4 signaling complex, whereas LPS of some non-enterobacterial organisms is capable of signaling independently of TLR4 utilizing TLR2-mediated signal transduction instead. In this study we report that Porphyromonas gingivalis LPS, a TLR2 agonist, fails to induce a fully endotoxin tolerant state in a human monocytic cell line (THP-1) and mouse bone marrow-derived macrophages. In contrast to significantly decreased production of human IL-8 and TNF-␣ and, in mice, keratinocyte-derived cytokine (KC), macrophage inflammatory protein-2 (MIP-2), and TNF-␣ after repeated challenge with Escherichia coli LPS, cells repeatedly exposed to P. gingivalis LPS responded by producing less TNF-␣ but sustained elevated secretion of IL-8, KC, and MIP-2. Furthermore, in endotoxin-tolerant cells, production of IL-8 is controlled at the signaling level and correlates well with NF-B activation, whereas TNF-␣ expression is blocked at the gene transcription level. Interferon ␤ plays an important role in attenuation of chemokine expression in endotoxin-tolerized cells as shown in interferon regulatory factor-3 knock-out mice. In addition, human gingival fibroblasts, commonly known not to display LPS tolerance, were found to be tolerant to repeated challenge by LPS if pretreated with interferon ␤. The data suggest that the inability of the LPS-TLR2 complex to induce full endotoxin tolerance in monocytes/macrophages is related to diminished production of interferon ␤ and may partly explain the involvement of these LPS isoforms in the pathogenesis of chronic inflammatory diseases.Detection of pathogen-associated molecular patterns by Toll-like receptors (TLRs) 2 expressed on innate immune cells triggers a robust and essential inflammatory reaction. Inflammation as a well coordinated process that comprises increased vascular permeability, migration of polymorphonuclear leukocytes, monocytes, and lymphocytes into affected tissues, and activation of cells to secrete inflammatory mediators is essential for host defense (1). If it is well controlled and resolved in a timely manner, it benefits the host by elimination of the invading pathogen. Otherwise, prolonged or excessive inflammation leads to chronicity and tissue damage (2).Toll-like receptors represent a family of evolutionarily highly conserved transmembrane molecules that act as pathogen recognition receptors. To date, 13 mammalian TLRs have been identified, and each appears to be required for responses to a different class of infectious pathogen (3). Almost immediately after microbes invade, microbial products signal through TLRs, broadly distributed on immune cells, activating these cells to produce proinflammatory cytokines, interferons, histamine, and antimicrobial peptides (4). Toll-like receptor signaling represents a principal molecular pathway for host in...

Porphyromonas gingivalis Outer Membrane Vesicles Induce Selective Tumor Necrosis Factor Tolerance in a Toll-Like Receptor 4- and mTOR-Dependent Manner

“…It was recently reported that TLR4 is superior to TLR2 in regard to IL-10 production because signaling via TRIF prevented degradation of IL-10 mRNA in macrophages (55). Furthermore, TRIF-dependent release of IFN-␤ has been implicated in endotoxin tolerance (56). However, the level of IFN-␤ induction by P. gingivalis is low and was previously suggested to depend on the presence of TLR7 (57).…”

Stroma: the forgotten cells of innate immune memory

“…Zaric et al . showed that induction of tolerance could be achieved in gingival fibroblasts if IFN‐β was provided . Such a reduction in inflammatory response may provide a break in the inflammatory cycle and facilitate the induction of resolution.…”

“…A possible example is periodontitis, in which microbiota and host immune responses conspire to produce the most common chronic inflammatory disease in the world [81]. Zaric et al showed that induction of tolerance could be achieved in gingival fibroblasts if IFN-b was provided [33]. Such a reduction in inflammatory response may provide a break in the inflammatory cycle and facilitate the induction of resolution.…”

Induction of endoplasmic reticulum stress under endotoxin tolerance increases inflammatory responses and decreases Pseudomonas aeruginosa pneumonia

“…ET is an important and evolutionarily conserved mechanism protecting host animals from the tissue damage caused by excessive inflammation after exposure to an endotoxin (e.g., LPS) . Nonetheless, ET also serves as a key mechanism for sustained immunosuppression that is associated with the mortality of patients with sepsis in late phases .…”